There are many optically active organic compounds which occur naturally. In many of these compounds with a physiologically active type, only one kind of enantiomer has a desired activity. The other kind of enantiomer without the desired activity does not have a physiological activity useful in organisms, and in addition, in some cases it is known to be rather toxic to organisms. Therefore, as a safe synthetic method of pharmaceuticals, the development of a process for synthesizing desired compounds, or optically active compounds with high optical purity which are used as their intermediates, has been desired.
Optically active alcohols are useful as asymmetric sources for the synthesis of various optically active materials. They are generally prepared by optical resolution of racemates, or by asymmetric synthesis which uses biological catalysts or asymmetric metal complexes as a catalyst. In particular, the preparation of optically active alcohols by asymmetric synthesis is considered to be an indispensable technology for the preparation of a large amount of optically active alcohols. (R)-3-quinuclidinol is one of the industrially useful optically active alcohols as a synthetic intermediate for optically active and physiologically-active compounds utilized in pharmaceuticals and agricultural chemicals or for liquid crystal materials. optically active 3-quinuclidinol is used as an important intermediate for various physiologically-active or pharmacologically-active ingredients in, for example, therapeutic agents for arteriosclerosis having a squalene-synthase inhibitory effect, bronchodilators having a muscarine-receptor antagonistic activity, and inhibitors of gastrointestinal motility. As a conventional process for the preparation of optically active 3-quinuclidinol, for example, a process by the resolution of an acetylated form of racemic 3-quinuclidinol using optically active tartaric acid followed by hydrolysis is known. However, to increase optical purity, complex operations including repetition of re-crystallization for more than several times are required. In addition, as a process to utilize microorganisms and enzymes, the following process is known: a substance such as racemic 3-quinuclidinol ester is used as a raw material, to which the microorganisms and enzymes listed below are reacted for the selective and asymmetric hydrolysis of (S)-3-quinuclidinol ester, so that the remaining (R)-3-quinuclidinol ester is hydrolyzed to obtain (R)-3-quinuclidinol; as microorganisms and enzymes, for example, subtilisin protease, Aspergillus- or Pseudomonas-derived esterolytic enzyme, or microorganisms and enzymes belonging to Aspergillus, Rhizopus, Candida or Pseudomonas are used. Also reported is a process wherein racemic 3-quinuclidinol ester is used as a raw material, and (R)-3-quinuclidinol ester is selectively asymmetric-hydrolized using mare serum esterase. Furthermore, a process using racemic 3-quinuclidinol as a raw material, wherein only (S) form are converted to (S)-3-quinuclidinyl butyric acid using subtilisin protease, so that (R) forms are prepared, is known. However, these processes have problems such as low optical purity or difficulty in mass production due to complex synthetic processes. Moreover, because any of these processes is a method to obtain a desired optical enantiomer by optical resolution of racemic 3-quinuclidionol, the other undesired enantiomer remains. Accordingly in these processes, additional processes are required for undesired enantiomers, such as a process to reverse the steric configuration of asymmetric carbons in an undesired enantiomer to convert it into the desired one, or a process to convert an undesired enantiomer into a racemate and to obtain the desired one by re-application of optical resolution; as a result, production cost increases. Thus, any of these processes is far from a simple, economically efficient and effective process for the preparation of (R)-3-quinuclidinol. Other known processes include a process for preparing optically active 3-quinuclidinol from 3-quinuclidinone utilizing asymmetric reductive reaction by microorganisms and enzymes. In these reactions, wild-type microorganisms are reacted to substrate compounds to directly produce optically active compounds. This reaction process is a one-step reaction, achieving significant simplification of the reaction process. However, problems such as low optical purity and low accumulation concentration of products still exist.
As a process to obtain optically active alcohol, there is a process for the asymmetric hydrogenation of prochiral carbonyl compounds in the presence of an asymmetric metal complex catalyst. As an example, a process for the asymmetric hydrogenation of carbonyl compounds in the presence of a ruthenium metal complex having an optically active diphosphine compound such as BINAP, etc. as the ligand, a base such as a hydroxide of alkali metal or alkaline earth metal, and an optically active 1,2-ethylenediamine-type diamine compound, is disclosed. In addition, a process for the hydrogenation of carbonyl compounds using a ruthenium complex having an optically active diphosphine compound such as BINAP, etc. and an optically active 1,2-ethylenediamine-type diamine compound as the ligands, is disclosed. Furthermore, it is reported in JP A No. 2003-252884 that when a ruthenium complex having an optically active phosphine compound such as SKEWPOHS, etc. and an optically active 1,2-ethylenediamine-type diamine compound as the ligands is used, various carbonyl compounds can be effectively hydrogenated; however, there is no mentioning of the application of this method to quinuclidinones.
As a synthetic method of optically active 3-quinuclidinol, JP A No. 9-194480 discloses a method for hydrogenating a quinuclidinone derivative selected from the compounds consisting of 3-quinuclidinone and its adduct with Lewis acid, and specific tertiary and quaternary salts corresponding therewith, in the presence of a rhodium, iridium or ruthenium complex having an optically active diphosphine compound as the ligand. However, when 3-quinuclidinone was asymmetrically hydrogenated, the enantiometric excess of the optically active 3-quinuclidinol obtained was extremely low at 20% or less. The enantiometric excess improved when tertiary and quaternary salts of 3-quinuclidinone were used, but complex processes for the conversion into tertiary and quaternary salts, and for the conversion into 3-quinuclidinol educts after hydrogenation were required. JP A No. 2003-277380 discloses a process for the preparation of optically active 3-quinuclidinol by hydrogenating 3-quinuclidinone, in the presence of an optically active ruthenium complex having an optically active bidentate diphosphine compound and an optically active 1,2-ethylenediamine-type diamine compound as the ligands, and a base. Another process to hydrogenate carbonyl compounds containing 3-quinuclidinone using a rhodium complex as a catalyst, wherein said complex has an optically active phosphine compound with ferrocene backbone and an optically active 1,2-ethylenediamine-type diamine compound, is also disclosed. However, these processes were not industrially satisfactory due to their low activity and low optical purity.